There is increasing evidence that circadian rhythm abnormalities are important in the pathophysiology of some affective and sleep disorders. The mechanism of aciton of antidepressant drugs may involve correction of circadian rhythm abnormalities. However, assessing the chronobiologic effects of drugs in humans has been impeded by problems with imprecise markers for circadian rhythms and by the confounding influence of time cues which entrain circadian rhythms to a 24-hour day. In blind people, the entraining effects of the light-dark cycle are eliminated, often resulting in autonomous (free-running) rhythms which reflect the intrinsic period of the endogenous biological clock (usually about 25 hours). Measuring melatonin onsets at biweekly intervals provides a convenient and efficient way to monitor the free-running rhythms. Our pilot studies have shown that the period (tau) of the free-running melatonin rhythm is remarkably consistent making it possible to efficiently detect drug-induced changes in the rhythm. Thus we were able to show that bedtime administration of both melatonin and triazolam phase advanced the rhythm (shifted it to an earier time). In this project we will identify blind people with free-running rhythms and will measure the effects of acute and prolonged administration of triazolam, melatonin and lithium on the melatonin rhythm. We anticipate that these chronobiologic effects of drugs in humans. This may lead to treatments for blind people who suffer bouts of insomnia and daytime sleepiness as a result of free-running rhythms. This information will also lead to new insight into the mechanism of action of psychotropic drugs which will potentially benefit sighted people who suffer circadian rhythm disturbances associated with sleep and mood disorders, shift work and jet lag.